Alzheimer's disease is a progressive neurocognitive disorder which, without preventive intervention, will affect 10% of the developed world's population (Hagnell et al, Neuropsychobiology 7:201 (1981); Katzman et al, Ann. Neurol. 25:317 (1989)). Susceptibility to the disease is strongly influenced by genes. Two forms of this disease have been attributed to mutations on chromosomes 14 and 21 that act as dominant genetic traits (Hardy, Nature Genet. 4:233 (1992), (Schellenberg et al, Science 258:668 (1992), St. George-Hyslop et al, Nature Genet. 2:330 (1992), Van Broeckhoven et al, Nature Genet. 2:335 (1992)). At least two additional forms of Alzheimer's disease are presumed to be provoked by mutations or polymorphisms located elsewhere in the genome (Pericak-Vance et al, Am. J. Hum. Genet. 48:1034 (1991); Schellenberg et al, Science 241:1507 (1988); Roses et al, Current Neurology 14, C. V. Mosby, Chicago (1994)). One such polymorphic locus on chromosome 19, APOE which encodes the lipid transport protein apolipoprotein E, strongly influences the risk of Alzheimer's disease (Corder et al, Science 261:921 (1993)) and its timing of expression (Corder et al, Nature Genet. (1994)). New genetic marker loci on chromosome 12 or elsewhere are believed to bear similar influence (Pericak-Vance et al, Neurobiology of Aging, Keystone Symposium (1997)).
Although genetic influences predominate in determining which individuals are at risk of developing Alzheimer's disease, it is clear from twin studies that environmental factors are also important (Nee et al, Neurology 37:359 (1987)); Gatz et al, J. Geront. Medical Sciences 52AM117-M125 (1997)). It is believed that such environmental factors, possibly including pharmacologic exposures, may influence the risk of Alzheimer's disease at a given age by accelerating or retarding the unfolding of the disease process (Breitner et al, Epidemiologic Reviews 17:39 (1995)). This explanation is supported by recent evidence which shows that anatomic and metabolic markers of incipient Alzheimer's disease are apparent at least a decade prior to the appearance of clinical symptoms (Ohm et al, Neuroscience 69:209 (1995); Ohm et al, Neuroscience 66:583 (1995); Reiman et al, N. Eng. J. Med. 334:752 (1996)). Non-demented fraternal twin research subjects who have the pathogenic ε4 allele at APOE also show mild cognitive deficit when compared with their co-twins who lack the ε4 allele, and pooled subjects with ε4 show mild cognitive deficits when compared with age-matched subjects from the same cohort (Reed et al, Arch. Neurol. 51:1189 (1994)). Thus, there is increasing agreement that, whatever its causes, the pathogenetic process of Alzheimer's disease includes an extended latent phase, a briefer prodromal phase (mild symptoms not sufficient for clinical diagnosis), and the clinically recognizable symptomatic phase of Alzheimer's disease proper (Plassman et al, Neurology 47:317 (1996)).
The symptoms of Alzheimer's disease appear typically between ages 65 and 90 (Breteler et al, Epidemiol. Rev. 14:59 (1992)). Symptoms include deterioration of cognition, memory and language. An agent which retards the progression of the latent or prodromal phase of Alzheimer's disease should therefore delay the appearance of symptoms (onset). Since later onset implies briefer and less severe symptoms, if any, before death (Breitner, Ann. Intern. Med. 115:601 (1991)), the identification of factors that retard the pathogenetic process and thus delay onset is important. In like manner, an agent that retards the progression of symptoms in clinically diagnosed Alzheimer's disease will also result in reduced disability and, possibly, extended life span. Prior to the present invention, no such agents were securely known, but prior use of glucocorticoids was shown in an exploratory study of twins to be associated with a delay in expression of the disease (Breitner et al, Neurology 44:227 (1994)). A particular method of case-control comparisons in affected twin pairs and other populations at high risk of Alzheimer's disease (Breitner et al, Am. J. Epidemiol. 131:246 (1991)) has resulted in the present invention which provides a novel and highly effective method of preventing Alzheimer's disease or delaying the onset or progression of its symptoms.